Method of treating movement disorders

ABSTRACT

GALLIC ACID, ITS SALTS AND ITS ALKYL ESTERS ARE UTILIZED IN THE TREATMENT OF INVOLUNTARY MOVEMENT DISORDERS. THE COMPOUNDS CAN BE ADMINISTERED ALONE OR IN COMBINATION, AS WITH L-DOPA IN THE TREATMET OF PARKINSONISM.

United States Patent 3,729,563 Patented Apr. 24, 1973 ment disorders canbe conveniently observed in laboratory models utilizing, for example,monkeys with mesencephalic lesions. In this method, described byGoldstein et al., Proc. Nat. Acad. Science, 63, No. 4, 1113 (1969)unilateral radio frequency lesions are induced in No Drawing.Continuation-impart of application Ser. No. 5 the Flmmal which thendevelops hypokinesia almost s,940, Jan. 26, 1970. This application Dec.8, 1970, modlately and a resting tremor Within a week, a y a Ser.No.96,295 drome comparable to the neuropathological profile en- Int. Cl.A61k 27/00 countered in human parkinsonism. After administration 424-2433 Clalms of a dose of 50 mg./kg. of butyl gallate, the tremor diminishesor completely disappears for a period of one ABSTRACT OF THE DISCLOSUREto two hours.

Gallic acid, its salts and its alkyl esters are utilized S1m1larresponses can be observed in actual clinical in the treatment ofinvoluntary movement disorders. The i Thus dose of to a 28 Y oldcompounds can be administered alone or in combination, patlent,suffenngfrom a Fa Huntlngtons chore? as with LDOPA in the treatment ofparkinsonism sulted in a remarkable diminishment of the choreiformmovements. In a second patient, a 43 year old female CROSS REFERENCEwith a six year progressive history of chorea and a family background ofHuntingtons chorea, choreiform Thls 1S a commuatlon'm'part of 5940 filedmovements ceased and remained absent upon treatment 1970' with butylgallate. A third patient with spasmodic torti- DETAILED DESCRIPTIONcollis, when placed on 250 mg. t.i.d. had almost complete This inventionpertains to the treatment of involuncessation of dystonic neckmovements. tary movement disorders such as parkinsonism, Hunting- Themethod of treating involuntary movement distons chorea, hyperkinesis,spasmotic torticollis and the orders with gallic acid, its salts and itsesters can also like. Treatment of such disorders is elfected throughthe be practiced in conjunction with other therapy. Most administrationof a daily dose of from about 5 mg./kg. importantly, it has been foundthat gallic acid, its salts to about 25 mg./kg. of a compound of theformula: and its esters potentiate the action of L-DOPA [L-3-(3,4-

H0 dihydroxyphenyl)alanine] in the treatment of parkin- 30 sonism.L-DOPA is known to be useful in this regard H0 000R but its use islimited by the high doses required and the resultant side effects,particularly choreiform moveo ments, which develop in patients on longterm therapy.

wherein R is hydrogen or alkyl or from 1 to 9 carbon The value of theutilization of these compounds in atoms, or, when R is hydrogen, apharmaceutically acconjunction with L-DOPA therapy can be observed inceptable nontoxic alkali metal, alkaline earth metal or l r ry m l as wll as in r p in a organic amine salt thereof, i.e. a salt of gallicacid. monkey having mesencephalic lesions, doses of L-DOPA Certain ofthese derivatives are known to have therup to 25 mg./kg. produced nochange in the tremor. At apeutic activity. For example, Sakurai et al.,J. Pharm. half this dose of L-DOPA however, 12.5 mg./kg., when Soc.Japan, 69, 434 (1949) describe some anthelmintic administered witheither 10 or 15 mg./kg. of butyl galactivity for several alkyl gallates.US. Pat. No. 3,462,534 late, the tremor diminished for 40 minutes. When12.5 describes psychotherapeutic activity, specifically antimg./kg. ofL-DOPA was administered with 20 mg./kg. depressant properties, for alkylgallates and gallacetol. of butyl gallate, the tremor ceased for from 40to 60 -In contrast to the latter use which involves exclusively minutes.In a second monkey, while 15 mg./kg. of L- mental disorders, the presentinvention is based on the DOPA had no effect, 25 mg./kg. of L-DOPAeffected finding that gallic acid, its salts and esters reduce or acessation of tremor for 30 minutes and a diminished alleviate thephysical body movements associated with a tremor for 45 minutes. Howeverwhen 15 mg./kg. of broad group of conditions generally referred to bythe butyl gallate were administered, substantially the same art asinvoluntary movement disorders. These include the efiiect was obtainedwith only 15 mg./ kg. of L-DOPA as akinesia, rigidity, tremorsassociated with parkinsonism, observed for 25 mg./kg. of L-DOPA alone,namely a the dystonic neck movements associated with spasmoticdiminished tremor for 40 minutes and a cessation of torticollis, thechoreiform movements encountered in tremor for 20 to 30 minutes.

Huntingtons chorea and a variety of movement disor- In actual clinicaltests, these compounds have been ders resulting from extrapyramidaldysfunction. shown to be effective in combatting the dose-related toxicMoreover, in contrast to the use of certain alkyl galeffects of L-DOPAtherapy. In nine patients, for example, lates as anthelmintics, thesecompounds to date have extreated with a daily dose of 750 mg. of butylgallate, not hibited no side effects when administered according to onlywas there a significant reduction in the dose of L- the described methodof utilizing the present invention. DOPA required, but also a remarkabledecrease in un- The activity of these compounds on involuntarymovewanted side-effects, as shown in Table I.

TABLE I -LDOPA L-DOPA and butyl gallate Patient ABODEFGHIJ'ABCDEFGHIJDoseL-DOPA(gra.ms) 1.5 2.5 5 5 6 7 5 6 4 6 1.0 2.0 2.0 2.0 5 3 4 4 5Al'mnrmnl 10131032210000001000 14110121010000000000 1313323323000101111103023122210001101010 13012213221101110111 2003001011000100101110000000200000000000 12021212210101011110 NOTE.-0=n0 observableabnormality; 1=minimal abnormality; 2=minimal to moderate abnormality;3=moderate to severe abnormality; 4= maximal abnormality.

Gallic acid, a salt thereof or an ester thereof 'prferably administeredorally as a treatment for involuntary movement disorders. This can beaccomplished through the use of any of the usual pharmaceutical forms,in-' cluding solid and liquid unit oral dosage forms such as tablets,capsules, powders, suspensions, solutions, syrups and the like,including sustained release preparations. The term unit dosage form asused in this specification and the claims refer to physically discreteunits to be administered in single or multiple dosage to humans, eachunit containing a predetermined quantity of active materials inassociation with the required diluent, carrier or vehicle. The quantityof active material is that calcu lated to produce the desiredtherapeutic elfect upon administration of one or more of such units in asingle or multiple dose regimen.

Powders are prepared by comminuting gallic acid, a salt thereof or anester thereof to a suitably fine size and mixing with a similarlycomminuted diluent pharmaceutical carrier' such as an ediblecarbohydrate material as for example, starch. sweetening, flavoring,preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. A lubricant such as talc, magnesiumstearate and calcium stearate can be added to the powder mixture as anad juvant before the filling operation; a glidant such as colloidalsilica may be added to improve flow properties; a disintegrating orsolubilizing agent may be added to improve the availability of themedicament when the capsule is ingested.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and disintegrant and pressing into tablets. A powdermixture is prepared by mixing the compound, suitably comminuted, with adiluent or base such as starch, sucrose, kaolin, dicalcium phosphate andthe like. The powder mixture can be granulated by wetting with a bindersuch as syrup, starch paste, acacia mucilage or solutions of cellulosicor polymeric materials and forcing through a screen. As an alternativeto granulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets, themedicaments canialso be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A protective coating consisting of a sealing coat ofshellac,'a coating of sugar or polymericmaterial and a polish coating ofwax can be provided. Dyestufl's can be added to these coatings todistinguish ditferent unit dosages.

Oral fluids such as syrups and elixirs can be prepared in unit dosageform so that a given quantity, e.g., a teaspoonful, contains apredetermined amount of the compound. Syrups can be prepared bydissolving the compound vin a suitably flavored aqueous sucrose solutionwhile elixirs are prepared through the use of a non-toxic alcoholicvehicle. Suspensions can be formulated by dispersing the medicament in anon-toxic vehicle in which it is insoluble.

When utilized-alone, gallic acid, a salt thereof or an ester thereof isgenerally administered in a single or multiple dose regimen so that thepatient receives a daily dose of from about mg./kg. to about 25 mgJkg.This range is however merely a guideline for in all cases the actualdose must be adjusted to the age, weight and condition of the patientand most importantly, titrated to the response observed. Thus, forexample, for a human Ingredient:

' 'Whefi utiliied in conjunction with IrDOPA'therapy;

and then begin the administration of the gallic acid, salt,

or ester. In: this fashion, the required close of L-DOPA, which willvary from patient to patient, can be significantly reduced with, asdescribed above, a significant reduction of elimination of side effects.

In the Practice of this method, one can employ gallic acid, a saltthereof or an alkyl ester thereof. The salts are those derived fromalkali metals, alkaline earth metals or organic amines, such as thesodium, potassium, calcium and those of ammonia, ethylamine,triethylamine, ethanolamine, diethylarninoethanol, ethylenediamine,piperidine, morpholine, 2-(piperidino )-ethanol, benzylamine, procaineand the like. Esters are those derived from gallic acid and straight orbranched chain alcohols having from 1 to 9 carbon atoms,-such as methylgallate, ethyl gallate, n-propyl gallate, isopropyl gallate, n-butylgallate, pentyl gallate, hexyl gallate, octyl gallate, nonyl gallate andthe like. The preferred form of gallic acid for the practice of thepresent invention is the npropyl and n-butylesters.

The following examples will serve to further typify the nature ofthepresent invention but should not be construed as a limitation thereof.

The lactose, corn starch and Cab-O-Sil are blended and granulated withan alcoholic solution of the stearic acid. This granulate is blendedwith the butyl gallate and the resulting blend is encapsulated in #0capsules.

EXAMPLE 2 Quantity/capsule, mg. Butyl gallate 8O Corn starch 80 The twoingredients are thoroughly blended and encapsulated in #4 capsules.

of average weight of 70 kg, if an .initial daily dose of about 500- mg.does not produce a satisfactory response,

w g ss s qbss vsdt EXAMPLE 3 Ingredient: Quantity/capsule, mg. L-DOPAButyl gallate 200 Corn starch 500 The foregoing ingredients are mixedand introduced into a two-piece #1 hard gelatin capsule.

The.L-DOPA,butyl gallate, corn starch and lactose .are thoroughlyblended and granulated with a 10% aqueaus solution of gel'atinQThe Wetgranulate is dried, screened and combined with the Cab-O-Sil andmagnesiurn stearate. This mixture is pressed into tablets suitable fororal administration of 100 mg. of L-DOPA and 300 mg. of butyl gallate.The tablets may be scored to permit he admi is rat on of fractionaldoses EXAMPLE 5 Ingredient: Quantity/capsule, mg. L-DOPA 500 Propylgallate 300 Corn starch 200 Lactose 200 Cab-O-Sil M5 400 Gelatin 5Magnesium stearate 1 The foregoing ingredients are combined inaccordance with the procedure described in Example 4 and pressed intotablets suitable for oral administration of 50 mg. of L-DOPA and 300 mg.of propyl gallate.

The first four ingredients are thoroughly mixed and granulated with aaqueous solution of soluble starch. This granulate is dried, mixed withmagnesium stearate and pressed into tablet cores which are coated withsugar.

What is claimed is:

1. The method of treating involuntary movement disorders which comprisesorally administering to a human suffering from such disorder in a singleor multiple dosage regimen, a daily dose of from about 5 mg./kg. toabout 25 mg./kg. of a compound of the formula:

HO 000R wherein R is hydrogen or alkyl of from 1 to 9 carbon atoms, or'when R is hydrogen, a pharmaceutically acceptable non-toxic alkalimetal, alkaline earth metal or organic amine salt thereof.

2. The method of claim 1 wherein R is propyl.

3. The method of claim 1 wherein R is butyl.

References Cited UNITED STATES PATENTS 3,462,534 8/1969 Greengard et a1424308 STANLEY I. FRIEDMAN, Primary Examiner US. Cl. X.R.

